Since the initial funding of this project in April 1995, data from this project have provided compelling evidence that decreases in growth hormone and IGF-1 levels in aged animals contribute to both brain, cerebrovascular and cardiac aging. In the proposed funding period, this project is designed to assess whether decreases in growth hormone and IGF-1 in aged animals contribute to a decline in vascular density and cerebral blood flow that alter the interstitial microenvironment contributing to an increase in oxidative stress and a corresponding reduction in glucose utilization and/or activity of neurons and gila. The following studies are proposed: 1. Assess whether growth hormone/ IGF-1 deficiency contribute to a reduction in brain blood flow and cerebral angiogenesis. Studies will analyze the effects of growth hormone/ IGF-1 on cerebral blood flow, and cerebrovascular density using young animals treated with IGF antagonists (IGFBP-2), older animals treated with growth hormone, and in a novel model of adult-onset growth hormone deficiency. 2. Determine whether growth hormone/ IGF-1 deficiency contribute to an increase in oxidative stress in the CNS. Studies will compare oxidative damage under basal conditions (and after treatment with growth hormone) and in a model of adult-onset growth hormone deficiency. In addition, the ability of growth hormone and IGF-1 to protect against damage resulting from acute oxidative stress will be assessed. 3. Determine whether the age-related decreases in glucose metabolism and neuronal activity are regulated by diminished levels of growth hormone and IGF-1. The effects of adult-onset growth hormone deficiency on cognitive function will be assessed and its relationship to decreases in cytochrome oxidase activity determined. Finally, the ability of growth hormone and IGF-1 to protect against the oxidative stress-induced decline in local cerebral glucose utilization and neuronal activity will be assessed. The results of these studies will be critical in assessing the inter-relationships between the decline in growth hormone and IGF-1, alterations in cerebrovasculature and functional changes in the brain with age that are precursors to agerelated disease, loss of cognitive function and the increased risk of dementia.